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Use of Umbilical Core Blood derived HSC to Treat Acute Kidney Injury

使用脐带血造血干细胞治疗急性肾损伤

基本信息

批准号：
7936898
负责人：
FANGMING LIN
金额：
$ 30.72万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7936898
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Aorta Area Autologous Blood Blood Banks Bone Marrow CD34 gene Cell Separation Cell Therapy Cells Chronic Kidney Failure Clinical Cost of Illness Dedications Developmental Gene End stage renal failure Ensure Epigenetic Process Epithelial Epithelial Cells Ethics Expenditure Goals Gonadal structure Hematopoiesis Hematopoietic Hematopoietic stem cells Histone Deacetylase Histone Deacetylase Inhibitor Hospitals Human Immunodeficient Mouse Immunosuppression In Vitro Incidence Infant Injection of therapeutic agent Injury Kidney Kidney Diseases Lead Measures Medicare Mesenchymal Mesonephric structure Monitor Morbidity - disease rate Mus Natural regeneration Phenotype Quality of life Recovery Recovery of Function Regenerative Medicine Reperfusion Injury Risk Safety Site Stem cells Structure Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Tissues Translating Translations Transplantation Trichostatin A Tubular formation Umbilical Cord Blood clinical application cytokine effective therapy experience improved innovation kidney cell mortality mouse model paracrine programs public health relevance repaired small molecule stem stem cell biology

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to take an innovative approach to develop cell therapeutic agents from human umbilical cord blood-derived hematopoietic stem cells (UCB-HSC) to treat acute kidney injury (AKI). Acute kidney injury not only has a high morbidity and mortality rate but often leads to chronic kidney disease. At the present time, there is no specific treatment for AKI. Once the kidney fails, treatment of chronic kidney disease costs 20% Medicare expenditure. New and more effective treatments, such as stem cell-based therapy, will have significant clinical and financial impact. We have shown that mouse bone marrow HSC can be reprogrammed into cells expressing renal developmental genes after 1 week of treatment with cytokines and nephrogenic factors in vitro. Further treatment of the cells with a histone deacetylase (HDAC) inhibitor trichostatin A (TSA) enhances reprogramming from 6% to 38%. Injection of the reprogrammed cells into mice with renal ischemic injury accelerates kidney structural and functional recovery. To begin to translate these findings clinically, we propose to reprogram human UCB- HSC and test their therapeutic effect in mouse models of AKI. Umbilical cord blood contains higher concentrations of CD34+ stem and progenitor cells. The cells can be isolated easily without risk to the donors. The UTSW-affiliated Parkland Memorial Hospital delivers about 47 infants a day, which ensures an abundant supply for cell isolation. Using a similar approach for the mouse bone marrow HSC, CD34+ cells from human umbilical cord blood will be treated in vitro with cytokines, nephrogenic factors and a HDAC inhibitor TSA to induce hematopoietic-to-renal conversion. The induced cells will be characterized for the expression of a panel of renal developmental genes, and their ability to differentiate into epithelial cells and form tubular structures (Aim 1). Furthermore, the induced cells will be transplanted into mice with acute ischemia-reperfusion injury to test whether they accelerate renal functional and structural recovery. The mechanisms of renal protection by direct cell replacement into the repairing tubules and/or paracrine effect to decrease epithelial and endothelial injury and increase intrinsic renal cell regeneration will be investigated (Aim 2). This project may represent the first step toward translation of stem cell biology to the bedside. We are confident that with our experience and dedication, we will be able to complete the studies in Aim 1 in the first 9 months and the studies in Aim 2 in the next 15 months. PUBLIC HEALTH RELEVANCE: Acute kidney injury has high morbidity and high mortality. There is no specific and effective treatment at the present time. Stem cells offer therapeutic potential for kidney disease. The goal of this application is to develop cell therapeutic agents from human umbilical cord blood-derived stem cells to treat acute kidney injury.

描述（由申请人提供）：本项目的总体目标是采用创新方法从人脐带血来源的造血干细胞（UCB-HSC）中开发细胞治疗药物，用于治疗急性肾损伤（阿基）。急性肾损伤不仅有很高的发病率和死亡率，而且往往导致慢性肾脏疾病。目前还没有针对阿基的具体治疗方法。一旦肾脏衰竭，慢性肾脏疾病的治疗费用为医疗保险支出的20%。新的和更有效的治疗方法，如基于干细胞的治疗，将产生重大的临床和经济影响。我们已经证明，在体外用细胞因子和造肾因子处理1周后，小鼠骨髓HSC可以重编程为表达肾发育基因的细胞。进一步用组蛋白脱乙酰酶（HDAC）抑制剂阿司他丁A（TSA）处理细胞，使重编程从6%提高到38%。将重编程细胞注射到肾缺血损伤的小鼠中促进肾脏结构和功能的恢复。为了开始将这些发现转化为临床结果，我们建议重编程人UCB- HSC并在阿基的小鼠模型中测试其治疗效果。脐带血含有较高浓度的CD 34+干细胞和祖细胞。细胞可以很容易地分离，而不会对供体造成风险。UTSW附属的帕克兰纪念医院每天运送大约47名婴儿，这确保了细胞分离的充足供应。使用用于小鼠骨髓HSC的类似方法，将在体外用细胞因子、肾生成因子和HDAC抑制剂TSA处理来自人脐带血的CD 34+细胞，以诱导造血向肾的转化。将表征诱导的细胞的一组肾发育基因的表达，以及它们分化成上皮细胞和形成管状结构的能力（目的1）。此外，诱导的细胞将被移植到急性缺血再灌注损伤的小鼠中，以测试它们是否加速肾功能和结构的恢复。将研究通过直接细胞替代进入修复小管和/或旁分泌效应以减少上皮和内皮损伤并增加内在肾细胞再生的肾保护机制（目的2）。这个项目可能代表了干细胞生物学向临床转化的第一步。我们有信心，凭我们的经验和努力，我们将能够在首9个月内完成目标1的研究，并在未来15个月内完成目标2的研究。公共卫生相关性：急性肾损伤具有高发病率和高死亡率。目前还没有具体有效的治疗方法。干细胞为肾脏疾病提供了治疗潜力。本申请的目的是从人脐带血来源的干细胞开发细胞治疗剂，以治疗急性肾损伤。